Oxathiane derivatives

ABSTRACT

Oxathiane derivatives of formula ##STR1## in which R represents alkyl and A represents optionally substituted phenyl or a heteroaromatic group containing 1 or 2 nitrogen atoms optionally substituted by alkyl, alkoxy or halogen, and salts thereof possess pharmacological activity and are also useful in inhibiting head hair loss.

This invention relates to new therapeutically useful oxathianederivatives, to processes for their preparation and to pharmaceuticalcompositions containing them.

The new oxathiane derivatives of the present invention are thosecompounds of formula (I), hereinafter depicted wherein:

R represents an alkyl group; and

A represents:

(1) a phenyl or naphthyl group which is optionally substituted by one ormore substituents selected from halogen atoms and cyano, nitro,trifluoromethyl, carbamoyl, carboxyl, alkoxycarbonyl, alkylsulphonyl,alkyl and phenylalkyl groups; or

(2) a heteroaromatic group containing 1 or 2 nitrogen atoms, for exampleselected from pyrid-3-yl, quinolin-3-yl, isoquinolin-4-yl,pyridazin-4-yl, pyrimidin-5-yl, pyrazin-3-yl, indol-3-yl andthiazol-5-yl, optionally substituted by an alkyl or alkoxy group, or ahalogen atom;

wherein all alkyl groups and moieties, including those in alkoxy andalkoxycarbonyl groups, are straight-chain or branched, and, unlessotherwise specified, contain one to about six carbon atoms; andpharmaceutically acceptable salts thereof.

Preferred values for A include 3,4-dichlorophenyl and 3-pyridyl and R ispreferably methyl.

When A represents an optionally substituted phenyl group it ispreferably a phenyl group which is unsubstituted or substituted on the3-position or on the 3- and 5-positions by substituents selected fromhalogen atoms and cyano, nitro, trifluoromethyl, carbamoyl, carboxyl,alkoxycarbonyl and alkylsulphonyl groups.

It is also preferred that the sulphoxide oxygen and the --CSNHR groupare in the trans relationship.

In certain cases the substituents A and R can contribute tostereoisomerism. All such forms are embraced by the present invention.

Particularly important compounds of the present invention include thefollowing:

A(±)-trans-3-(3,4-dichlorophenyl)-N-methyl-1,4-oxathiane-3-carbothioamide4-oxide

B (±)-trans-N-methyl-3-(3-pyridyl)-1,4-oxathiane-3-carbothioamide4-oxide.

as well as their stereoisomeric forms and pharmaceutically acceptablesalts thereof.

Letters A and B are allocated to compounds for ease of reference inother parts of the specification.

The compounds have valuable pharmacological properties, in particularproperties which are indicative of utility in the treatment and/orprophylaxis of disorders associated with:

(1) vascular smooth muscle contraction including hypertension and othercardiovascular disorders such as congestive heart failure, andconditions associated with tissue ischaemia such as angina, peripheralvascular disease and cerebrovascular disease;

(2) respiratory smooth muscle contraction including reversible airwaysobstruction and asthma;

(3) contraction of smooth muscle of gastrointestinal tract, urinarybladder and uterus, including peptic ulcers, irritable bowel syndromeand diverticular disease; irritable bladder syndrome; and prematurelabour.

The compounds also have utility in the inhibition of head hair lossassociated with male pattern baldness, by topical application.

Compounds within the scope of the present invention exhibit positivepharmacological activities as demonstrated by in vitro tests which arebelieved to correlate to pharmacological activity in humans and otheranimals.

For example, compounds of general formula (I) were submitted to:

VASO-RELAXANT ACTIVITY TEST

The test method used was adapted from those described by Winslow et al[Eur.J.Pharmacol., 131, 219-228 (1986)] and Karaki [J.Pharmacol.Methods, 18, 1-21 (1987)] for differentiating vaso-relaxant activity.

Thoracic aorta was removed from rats and transverse strips, denuded ofendothelium, were suspended in a bath containing Krebs solution. Thetension was recorded and a contraction induced by addition of 20 mM K⁺(potassium ion) to the bathing solution. The test compound was added tothe bath as a solution in increasing cumulative concentration. Theconcentration in the bathing solution of the test compound which reducedthe K⁺ -induced contraction by 90% was determined and expressed in μM asthe effective concentration (EC₉₀), given in Table 1.

                  TABLE 1                                                         ______________________________________                                               Compound                                                                              EC.sub.90 μM                                                ______________________________________                                               A       0.3                                                                   B       2                                                              ______________________________________                                    

The compounds of general formula (I) can be prepared by the applicationand adaptation of known methods, for example as hereinafter identified.By the term "known methods" as used in this specification is meantmethods heretofore used or described in the literature.

According to a feature of the present invention, the compounds ofgeneral formula (I), wherein A and R are as hereinbefore defined, areprepared by the reaction of a compound of formula (II), wherein A is ashereinbefore defined and R¹ is alkyl, as hereinbefore defined, or abenzyl or carboxymethyl radical, with a compound of formula:

    R--NH.sub.2                                                (III)

wherein R is as hereinbefore defined.

The reaction is generally carried out using an excess of amine (III),without a solvent, or in an inert organic solvent such as an ether, anaromatic hydrocarbon, an alcohol (e.g. ethanol) or dimethylsulphoxide,or a mixture of these solvents normally at room temperature, optionallyunder pressure and optionally in the presence of thiol acceptor, such asa heavy metal salt (e.g. mercuric chloride). The amine may be added as asolution in an alcohol (e.g. ethanol).

Compounds of formula (II), wherein A and R¹ are as hereinbefore defined,can be prepared by the reaction of compounds of formula (IV), wherein Ais as hereinbefore defined, with carbon disulphide, followed by reactionwith a compound of formula:

    R.sup.1 --X                                                (V)

wherein R¹ is as hereinbefore defined and X is halogen, preferablyiodine or a readily displaceable ester groups such asmethanesulphonyloxy or 4-toluenesulphonyloxy.

The reaction is generally carried out in an anhydrous, inert, organicsolvent such as dimethylformamide, at a temperature from -70° C. to roomtemperature, and in the presence of an organic base such as a potassiumalkoxide (e.g. the tert-butoxide), or an organolithium compound, orsodium hydride.

Compounds of formula (IV), wherein A is as hereinbefore defined, can bemade by oxidation of the corresponding compounds of formula (VI). Thisis typically by reaction with a peroxy acid (e.g. meta-chloroperbenzoicacid) in an inert solvent, such as dichloromethane, at or below roomtemperature.

Compounds of formula (VI), wherein A is as hereinbefore defined, can beprepared by the reaction of a compound of formula:

    AMgBr                                                      (VII)

wherein A is as hereinbefore defined (usually prepared from thecorresponding bromide by conventional means), with3-chloro-1,4-oxathiane.

This is typically carried out in an inert solvent such as benzene, at orbelow room temperature.

Alternatively, compounds of formula (IV) can be prepared by the reactionof compounds of formula:

    A--CH.sub.2 --S(O)--(CH.sub.2).sub.2 --OH                  (VIII)

wherein A is as hereinbefore defined, with formaldehyde.

This reaction is generally carried out in an inert solvent such asdimethylformamide, in the presence of an organic base, such as potassiumtert-butoxide, and under ice cooling.

Compounds of formula (VIII), wherein A is as hereinbefore defined, canbe prepared by the oxidation of the corresponding compounds of formula:

    A--CH.sub.2 --S--(CH.sub.2).sub.2 --OH                     (IX)

wherein A is as hereinbefore defined, generally under conditions similarto those described above for the conversion of compounds of formula (VI)to those of formula (IV).

Compounds of formula (IX), wherein A is as hereinbefore defined, can beprepared by the reaction of a compound of formula:

    A--CH.sub.2 --X.sup.1                                      (X)

or a salt thereof, wherein A is as hereinbefore defined and X¹ is ahalogen, preferably chlorine, atom, with 2-mercaptoethanol.

This reaction is typically carried out in an inert organic solvent suchas an alcohol (e.g. ethanol), in the presence of an organic base (e.g.sodium ethoxide), at temperatures up to reflux.

Compounds of formulae (III), (V), (VII) and (X) can be made byapplication or adaptation of known methods or are readily available.

It will be understood that it may be desirable to change one or more ofthe substituents on the aryl groups at an appropriate stage during thesynthesis of the compounds of the invention. For example, the compoundsof general formula (I) wherein A represents a phenyl group substitutedby a carbamoyl group may be alternatively prepared from thecorresponding compounds of general formula (I) wherein A represents aphenyl group substituted by a cyano group by the application oradaptation of known methods for such conversion.

By the term "pharmaceutically acceptable salts" as used in thisspecification is meant salts the anions or cations of which arerelatively innocuous to the animal organism when used in therapeuticdoses so that the beneficial pharmaceutical properties of the parentcompounds of general formula (I) capable of forming salts are notvitiated by side-effects ascribable to those anions or cations.

It is to be understood that, where in this specification reference ismade to compounds of formula (I), it is intended to refer also, wherethe context so permits, to their pharmaceutically acceptable salts.

Suitable acid addition salts for use in pharmaceuticals may by selectedfrom salts derived from inorganic acids, for example hydrochlorides,hydrobromides, phosphates, sulphates and nitrates, and organic acids,for example oxalates, lactates, tartrates, acetates, salicylates,citrates, propionates, succinates, fumarates, maleates,methylene-bis-β-hydroxynaphthoates, gentisates anddi-p-toluoyltartrates.

Suitable salts with bases include alkali metal (e.g. sodium andpotassium), alkaline earth metal (e.g. calcium and magnesium), ammoniumand amine (e.g. diethanolamine, triethanolamine, octylamine, morpholineand dioctylmethylamine) salts.

As well as being useful in themselves as active compounds,pharmaceutically acceptable salts of the compounds of general formula(I) capable of forming salts with acids or bases are useful for thepurposes of purification of the parent compounds of general formula (I),for example by exploitation of the solubility differences between thesalts and the parent compounds, by techniques well known to thoseskilled in the art.

The thioformamide derivatives of general formula (I) obtained by theaforedescribed processes can be purified by the usual physical methods,in particular crystallisation and chromatography, especially to resolvemixtures of enantiomers using a chiral column. ##STR2##

The following Examples illustrate the preparation of compounds accordingto the present invention.

EXAMPLE 1 Compound A

A suspension of(±)-trans-3-(3,4-dichlorophenyl)-3-methylthiothiocarbonyl-1,4-oxathiane4-oxide (730 mg, 2 mmol) in ethanol (20 ml) and dimethylsulphoxide (2.8ml) was treated with methylamine solution (1.5 ml, 33% in ethanol, 15.7mmol) and the mixture stirred for 1.5 hrs at room temperature. Themixture was then evaporated in vacuo and partitioned betweendichloromethane (25 ml) and water (25 ml). The organic layer was dried(MgSO₄) evaporated in vacuo and purified by flash chromatography onsilica, eluting with ethyl acetate to give(±)-trans-3-(3,4-dichlorophenyl)-N-methyl-1,4-oxathiane-3-carbothioamide4-oxide (220 mg), as colourless crystalline solid, m.p. 213°-214° C.;

[Found: C, 43.0; H, 4.07; Cl, 19.6% Calculated for C₁₂ H₁₃ Cl₂ NO₂ S₂ :C, 42.6; H, 3.87; Cl, 20.7%].

EXAMPLE 2 Compound B

A stirred solution of(±)-trans-3-(3-pyridyl)-3-methylthiothiocarbonyl-1,4-oxathiane 4-oxide(560 mg, 1.9 mmol) in ethanol (30 ml) at room temperature was treatedwith a solution of methylamine (33% in ethanol, 4 ml) and the mixturestirred at room temperature for 30 mins. The mixture was evaporated invacuo and purified by flash chromatography on silica, eluting with 5%methanol in dichloromethane, to give(±)-trans-N-methyl-3-(3-pyridyl)-1,4-oxathiane-3-carbothioamide 4-oxide(220 mg), m.p. 159°-161° C.;

[Found: C, 48.9; H, 5.29; N, 10.4% Calculated for C₁₁ H₁₄ N₂ O₂ S₂ : C,48.86; H, 5.21; N, 10.36%].

REFERENCE EXAMPLE 1

A stirred solution of 3-(3,4-dichlorophenyl)-1,4-oxathiane 4-oxide (amixture of cis/trans isomers) (265 mg, 1 mmol) in dimethylformamide (5ml), under argon, was cooled to -40° C. and treated with potassiumtert-butoxide (0.12 g, 1.1 mmol). After 40 mins at this temperature asolution of carbon disulphide (84 mg, 1.1 mmol) in dimethylformamide(0.5 ml) was added and the resulting red solution stirred for a further1 hour. A solution of methyl iodide (156 mg, 1.1 mmol) indimethylformamide (0.5 ml) was added and the resulting solution stirredfor a further 2 hours. The reaction mixture was then poured into amixture of dichloromethane (25 ml) and aqueous ammonium chloridesolution (25 ml). The organic layer was separated, dried (MgSO₄) andevaporated in vacuo to provide an orange oil which was purified by flashchromatography on silica, eluting with 25% ethyl acetate in toluene, togive(±)-trans-3-(3,4-dichlorophenyl)-3-methylthiothiocarbonyl-1,4-oxathiane4-oxide (0.11 g), as orange crystals m.p. 147°-150° C.

REFERENCE EXAMPLE 2

A stirred solution of 3-(3,4-dichlorophenyl)-1,4-oxathiane (1 g, 4 mmol)in dichloromethane (10 ml) at 0° C. was treated with a solution ofmeta-chloroperoxybenzoic acid (85%, 860 mg, 4 mmol) in dichloromethane(10 ml) and stirred at 0° C. for 30 mins then at room temperature for 3hrs. The mixture was shaken with aqueous sodium bicarbonate solution andthe organic phase separated, dried (MgSO₄) and evaporated to give asolid which was triturated with hexane/toluene (1:1) to give3-(3,4-dichlorophenyl)-1,4-oxathiane 4-oxide (860 mg), as a colourlesscrystalline solid, m.p. 100°-103° C.;

[Found: C, 45.5; H, 3.8; Cl, 26.9% Calculated for C₁₀ H₁₀ Cl₂ OS: C,45.3; H, 3.8; Cl, 26.7%].

REFERENCE EXAMPLE 3

A stirred solution of 3,4-dichlorophenylmagnesium bromide [prepared from3,4-dichlorobromobenzene (10.2 g, 45 mmol) and magnesium (1.1 g, 45mmol) in the usual fashion] was treated with a solution of3-chloro-1,4-oxathiane [prepared from 1,4-oxathiane (2.6 g, 25 mmol)using the method of Tuleen and Bennet J. Het. Chem. 1969, 6, 115] inbenzene (30 ml), maintaining the temperature of reaction below 10° C.The mixture was allowed to stand at room temperature overnight. It wasthen poured into ammonium chloride solution (50 ml), the organic phasewas separated and the aqueous washed with ether (2×40 ml). The combinedorganic extracts were dried (MgSO₄) and purified by flash chromatographyon silica eluting with toluene/hexane (1:1) to give3-(3,4-dichlorophenyl)-1,4-oxathiane (4.5 g), as colourless crystals,m.p. 65°-68° C.;

[Found: C, 48.6; H, 4.05; Cl, 28.3; S, 12.7% Calculated for C₁₀ H₁₀ Cl₂OS: C, 48.32; H, 4.05; Cl, 28.5; S, 12.9%].

REFERENCE EXAMPLE 4

A solution of carbon disulphide (216 mg, 2.8 mmol) and3-(3-pyridyl)-1,4-oxathiane 4-oxide (280 mg, 1.4 mmol) indimethylformamide (1 ml) was cooled and added to a solution of potassiumtert-butoxide (320 mg, 2.8 mmol) in dimethylformamide (20 ml) in a dryice/acetone bath at -70° C. After 5 mins a solution of methyl iodide(403 mg, 2.8 mmol) in dimethylformamide (1 ml) was added. After 30 minthe mixture was poured into ethanol (50 ml) and evaporated in vacuo. Theresidue was purified by flash chromatography eluting with 3% methanol indichloromethane to give(±)-trans-3-(3-pyridyl)-3-methylthiothiocarbonyl-1,4-oxathiane 4-oxide(180 mg), as an orange oil.

REFERENCE EXAMPLE 5

A stirred solution of 2-(3-pyridylmethylsulphinyl)ethanol (0.25 g, 1.35mmol) in dimethylformamide (25 ml) at 0° C. was treated portionwise withpotassium tert-butoxide (0.15 g, 1.35 mmol) and stirred for 10 mins.Formaldehyde gas [generated by heating paraformaldehyde (45 mg, 1.5mmol) at 150° C.] was passed into the reaction mixture in a rapid streamof argon whilst cooling in an ice bath. When addition of theformaldehyde was completed the cooling bath was removed and the mixtureallowed to warm to room temperature over 15 mins. The solution waspoured into ethanol (30 ml), neutralised with concentrated hydrochloricacid and filtered to give a clear solution which was evaporated in vacuoand the residue was purified by flash chromatography on silica, elutingwith 7% methanol in dichloromethane, to give 3-(3-pyridyl)-1,4-oxathiane4-oxide (900 mg), as a colourless crystalline solid, m.p. 74°-76° C.

REFERENCE EXAMPLE 6

A stirred solution of 2-(3-pyridylmethylthio)ethanol (3.38 g, 20 mmol)in dichloromethane (50 ml) at 0° C. was treated dropwise with a solutionof m-chloroperoxybenzoic acid in dichloromethane (50 ml). The mixturewas stirred at 0° C. for 1 hr and at room temperature for 3 hrs. Themixture was evaporated in vacuo and purified by flash chromatography onsilica eluting with 20% methanol in ethyl acetate to give2-(3-pyridylmethylsulphinyl)ethanol (3.5 g), as colourless crystals,m.p. 84°-86° C.;

[Found: C, 51.9; H, 6.14; N, 7.6; S, 17.2% Calculated for C₈ H₁₁ NO₂ S:C, 51.85; H, 5.98; N, 7.6; S, 17.3%].

REFERENCE EXAMPLE 7

A stirred solution of sodium ethoxide (4.6 g of sodium in 100 mlethanol) was treated with 2-mercaptoethanol (7.8 g, 0.1 mol) followed by3-chloromethylpyridine hydrochloride (16.4 g, 0.1 mol). The mixture wasthen refluxed under argon for 3.5 hours, filtered and evaporated invacuo and the residue purified by flash chromatography on silica,eluting with 3% methanol in ethyl acetate, to give2-(3-pyridylmethylthio)ethanol (13 g), as a yellow oil;

[Found: C, 56.3; H, 6.6; N, 8.2; S, 18.8% Calculated for C₈ H₁₄ NOS: C,56.8; H, 6.55; N, 8.27; S, 18.9%].

The present invention includes within its scope pharmaceuticalcompositions which comprise a compound of general formula (I) or apharmaceutically acceptable salt thereof, in association with apharmaceutically acceptable carrier or coating. In clinical practice thecompounds of the present invention may be administered rectally, but arepreferably administered parenterally, by inhalation if appropriate, or,more preferably, orally.

Solid compositions for oral administration include compressed tablets,pills, powders and granules. In such solid compositions, one or more ofthe active compounds is, or are, admixed with at least one inert diluentsuch as starch, sucrose or lactose.

The compositions may also comprise, as is normal practice, additionalsubstances other than inert diluents, e.g. lubricating agents, such asmagnesium stearate.

Liquid compositions for oral administration include pharmaceuticallyacceptable emulsions, inert diluents commonly used in the art such aswater and liquid paraffin. Besides inert diluents such compositions maycomprise adjuvants, such as wetting, and suspending agents, andsweetening, flavouring, perfuming and preserving agents. Thecompositions according to the invention for oral administration alsoinclude capsules of absorbable material such as gelatin, containing oneor more of the active substances with or without the addition ofdiluents or excipients.

Compositions according to the invention for parenteral administrationinclude sterile aqueous, aqueous-organic, and organic solutions,suspensions and emulsions. Examples of organic solvents or suspendingmedia are propylene glycol, polyethylene glycol, vegetable oils such asolive and injectable organic esters such as ethyl oleate. Thecompositions may also contain adjuvants such as stabilising, preserving,wetting, emulsifying and dispersing agents. They may be sterilised by,for example, filtration through a bacteria-retaining filter, byincorporation in the compositions of sterilizing agents, by irradiationor by heating. They may also be manufactured in the form of sterilesolid compositions, which can be dissolved in sterile water or someother sterile injectable medium immediately before use.

Compositions for inhalation may be sterile aqueous solutions which arethen nebulised or dry powders formulated in accordance with knownmethods.

Solid compositions for rectal administration include suppositoriesformulated in accordance with known methods and containing one or moreof the compounds of formula (I) or a pharmaceutically acceptable saltthereof.

The percentage of active ingredient in the composition of the inventionmay be varied, it being necessary that it should constitute a proportionsuch that a suitable dosage shall be obtained. Obviously, several unitdosage forms may be administered at about the same time. The doseemployed will be determined by the physician, and depends upon thedesired therapeutic effect, the route of administration, the duration ofthe treatment and the condition of the patient. In the adult, the dosesare generally from about 0.001 to about 50, preferably from about 0.01to about 5, mg/kg body weight per day by oral administration. Byinhalation, either as a nebulised solution or as a formulated drypowder, the preferred daily dosage is from about 0.001 to about 5,preferably from about 0.01 to about 0.5, mg/kg body weight.

The compounds may also be applied topically for inhibition of head hairloss associated with male pattern baldness, the preferred daily dosagebeing from 0.1 to 10 mg/kg body weight applied, for example, in 5 mlportions two or three times per day.

The following Example illustrates pharmaceutical compositions accordingto the present invention.

COMPOSITION EXAMPLE

No. 2 size gelatin capsules each containing:

    ______________________________________                                        (±)-trans-3-(3,4-dichlorophenyl)-N-methyl-1,4-                                                         20 mg                                             oxathiane-3-carbothioamide 4-oxide                                            lactose                    100 mg                                             starch                      60 mg                                             dextrin                     40 mg                                             magnesium stearate          1 mg                                              ______________________________________                                    

were prepared in accordance with the usual procedure.

We claim:
 1. A compound of the formula ##STR3## where R is lower alkyland A is pyridyl unsubstituted or substituted by lower alkyl, loweralkoxy or halo; or a pharmaceutically acceptable salt thereof.
 2. Acompound according to claim 1 where the --CSNHR group is trans to theoxygen atom attached to sulfur.
 3. A compound according to claim 1 whereR is methyl.
 4. A compound according to claim 1 where A is pyrid-3-yl.5. A compound according to claim 4 which is(+)-trans-N-methyl-3-(3-pyridyl)-1,4-oxathian-3-carbothioamide-4-oxide,or a pharmaceutically acceptable salt thereof.
 6. A pharmaceuticalcomposition for use in the treatment or prophylaxis of a disorder inneed of vaso-relaxant activity which composition comprises atherapeutically effective amount of a compound of claim 1 in an amounteffective to relax vascular smooth muscle in association with apharmaceutically acceptable carrier or diluent.